Objective models for steroid binding sites of human globulins

We report the application of a recently developed alignment-free 3D QSAR method [Crippen, G.M., J. Comput. Chem., 16 (1995) 486] to a benchmark-type problem. The test system involves the binding of 31 steroid compounds to two kinds of human carrier protein. The method used not only allows for arbitrary binding modes, but also avoids the problems of traditional least-squares techniques with regard to the implicit neglect of informative outlying data points. It is seen that models of considerable predictive power can be obtained even with a very vague binding site description. Underlining a systematic, but usually ignored, problem of the QSAR approach, there is not one unique type of model but, rather, an entire manifold of distinctly different models that are all compatible with the experimental information. For a given model, there is also a considerable variation in the found binding modes, illustrating the problems that are inherent in the need for 'correct' molecular alignment in conventional 3D QSAR methods.